Serotonin-induced vascular permeability is mediated by transient receptor potential vanilloid 4 in the airways and upper gastrointestinal tract of mice

• Published in: Laboratory investigation 2021-07, Vol.101 (7), p.851
• Main Authors: Retamal, Jeffri S, Grace, Megan S, Dill, Larissa K, Ramirez-Garcia, Paulina, Peng, Scott, Gondin, Arisbel B, Bennetts, Felix, Alvi, Sadia, Rajasekhar, Pradeep, Almazi, Juhura G, Carbone, Simona E, Bunnett, Nigel W, Davis, Thomas P, Veldhuis, Nicholas A, Poole, Daniel P, McIntyre, Peter
• Format: Article
• Language: English
• ISSN: 1530-0307

Endothelial and epithelial cells form physical barriers that modulate the exchange of fluid and molecules. The integrity of these barriers can be influenced by signaling through G protein-coupled receptors (GPCRs) and ion channels. Serotonin (5-HT) is an important vasoactive mediator of tissue edema and inflammation. However, the mechanisms that drive 5-HT-induced plasma extravasation are poorly defined. The Transient Receptor Potential Vanilloid 4 (TRPV4) ion channel is an established enhancer of signaling by GPCRs that promote inflammation and endothelial barrier disruption. Here, we investigated the role of TRPV4 in 5-HT-induced plasma extravasation using pharmacological and genetic approaches. Activation of either TRPV4 or 5-HT receptors promoted significant plasma extravasation in the airway and upper gastrointestinal tract of mice. 5-HT-mediated extravasation was significantly reduced by pharmacological inhibition of the 5-HT receptor subtype, or with antagonism or deletion of TRPV4, consistent with functional interaction between 5-HT receptors and TRPV4. Inhibition of receptors for the neuropeptides substance P (SP) or calcitonin gene-related peptide (CGRP) diminished 5-HT-induced plasma extravasation. Supporting studies assessing treatment of HUVEC with 5-HT, CGRP, or SP was associated with ERK phosphorylation. Exposure to the TRPV4 activator GSK1016790A, but not 5-HT, increased intracellular Ca in these cells. However, 5-HT pre-treatment enhanced GSK1016790A-mediated Ca signaling, consistent with sensitization of TRPV4. The functional interaction was further characterized in HEK293 cells expressing 5-HT to reveal that TRPV4 enhances the duration of 5-HT-evoked Ca signaling through a PLA and PKC-dependent mechanism. In summary, this study demonstrates that TRPV4 contributes to 5-HT -induced plasma extravasation in the airways and upper GI tract, with evidence supporting a mechanism of action involving SP and CGRP release. Serotonin (5-HT) is an important mediator of tissue edema and inflammation. The authors used mouse models and cell-based signaling assays to provide greater understanding of the mechanisms involved. They demonstrate that effects of 5-HT are mediated through the 5-HT receptor and involve activation of the mechanosensitive ion channel TRPV4 and neuropeptide release.